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FEBS Letters 584 (2010) 2279–2284

journal homepage: www.FEBSLetters.org

Evolution of 11b-hydroxysteroid dehydrogenase-type 1 and 11b-hydroxysteroid dehydrogenase-type 3

Michael E. Baker *

Department of Medicine, 0693, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, USA

article info abstract

Article history: A key regulator of action is 11b-hydroxysteroid dehydrogenase-type 1 (11b-HSD1), Received 15 February 2010 which catalyzes the conversion of to , the biologically active glucocorticoid. 11b- Revised 18 March 2010 HSD1 is a paralog of 11b-HSD3, whose physiological function remains unclear. As reported here, Accepted 24 March 2010 11b-HSD3 has orthologs in sea urchin, amphioxus and Ciona, while 11b-HSD1 first appears in sharks. Available online 27 March 2010 Thus, 11b-HSD3 arose before the evolution of glucocorticoid signaling, suggesting different ancestral Edited by Takashi Gojobori function(s) for 11b-HSD3. Four perplexing findings arise from this evolutionary analysis: (1) 11b- HSD1 is not present in a ray-finned fish genome, (2) zebrafish and fathead minnow contain two iso- forms of 11b-HSD3; (3) neither rat nor mouse contain 11b-HSD3 and (4) amphioxus contains 16 11b- Keywords: 11b-Hydroxysteroid dehydrogenase-type 3 HSD3 paralogs. 11b-Hydroxysteroid dehydrogenase-type 1 Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Evolution Amphioxus Sea urchin 11-Keto-testosterone

1. Introduction The evolution of 11b-HSD1 as a regulator of glucocorticoid ac- tion and as a partner with 11b-HSD2 in regulating glucocorticoid , such as cortisol and corticosterone, have di- and action are still not fully understood. In verse physiological roles in vertebrates, including regulating the 2004, a phylogenetic analysis found that 11b-HSD1 is a paralog immune response, , neural activity and bone formation of 11b-HSD3 [24], and that 11b-HSD3 is the ancestor of 11b- [1–4]. Local concentrations of cortisol and corticosterone are regu- HSD1. A perplexing finding was that 11b-HSD1 was not found in lated by two distinct 11b-hydroxysteroid dehydrogenases (11b- teleosts (ray-finned fish), which, instead, contain 11b-HSD3 [24]. HSDs): 11b-HSD-type 1 (11b-HSD1) and 11b-HSD2. 11b-HSD1, an The absence of 11b-HSD1 in fish could have been due to the limited NADPH-dependent , reduces the C11-ketone on cortisone number of fish genes in GenBank in 2004. Also unresolved were and 11-dehydrocorticosterone to an alcohol, yielding cortisol and when 11b-HSD1 and 11b-HSD3 first evolved. Did 11b-HSD1 first corticosterone, respectively [3] (Fig. 1). 11b-HSD2, an NAD+- appear in vertebrates, and, if so, at what stage of vertebrate evolu- dependent enzyme, oxidizes the C11-alcohol on cortisol and corti- tion? Or does 11b-HSD1 have a more ancient ancestry? Similar costerone to a ketone. Together, 11b-HSD1 and 11b-HSD2 com- questions arise regarding the evolution of 11b-HSD3. A key ques- prise an essential enzyme-based mechanism for regulating tion is whether the evolution of 11b-HSD1 and 11b-HSD3 coin- tissue-specific glucocorticoid and mineralocorticoid action [5,6]. cided with the evolution of glucocorticoid signaling. In addition to regulating the synthesis of glucocorticoids, 11b- This is an opportune time to reinvestigate these questions be- HSD1 metabolizes various 7-keto-sterols and 7-keto- cause since 2004, the medaka and stickleback genomes have been [7–13], including 7-keto- [11,14,15] and 7-keto-dehy- sequenced. In addition, the genomes from sea urchin, a basal deu- droepiandrosterone (DHEA) [10,16,17] (Fig. 1). Over-expression terostome and amphioxus, a basal chordate, have been sequenced of 11b-HSD1 in fat cells leads to metabolic syndrome [18–20]. (Fig. 2) and the Ciona and Fugu genomes have been updated. As a 11b-HSD1 also detoxifies xenobiotics by reducing their keto- result, there is a more complete genomic dataset for analysis of the groups [13,21–23] (Fig. 1). Thus, the physiological actions of 11b- origins of 11b-HSD1 and 11b-HSD3. HSD1 are diverse and complex. As reported here, a search of GenBank and other databases finds that 11b-HSD3 has orthologs in sea urchin, amphioxus and Ciona,

* Fax: +1 858 822 0873. while 11b-HSD1 first appears in a shark, supporting the previous E-mail address: [email protected] conclusion that 11b-HSD3 is the ancestor of 11b-HSD1. Thus far,

0014-5793/$36.00 Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2010.03.036 2280 M.E. Baker / FEBS Letters 584 (2010) 2279–2284

Fig. 1. Reactions catalyzed by 11b-hydroxysteroid dehydrogenase-type 1. 11b-HSD1, an NADPH-dependent enzyme, reduces the C11-ketone on cortisone and 11-keto- testosterone to yield cortisol and 11b-hydroxy-testosterone, respectively. 11b-HSD1 also metabolizes 11-keto-DHEA and 7-keto-cholesterol. Hamster 11b-HSD1 catalyzes the conversion of 7-keto-cholesterol to 7b-OH-cholesterol and 7a-OH-cholesterol [14]. Thus, species-specific differences in the stereochemistry of the C7-hydroxyl need to be considered. 11b-HSD1 also reduces the N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) [21]. NNK is a carcinogen in cigarette smoke. Also shown are reactions catalyzed by 11b-HSD2, an NAD+-dependent enzyme. neither glucocorticoid receptors nor glucocorticoids have been AAP42286) to search GenBank (www.ncbi.nlm.nih.gov/entrez), found in sea urchin, amphioxus or Ciona [25]. This suggests that Ensembl (http://www.ensembl.org/), elephant shark server (http:// in these organisms, 11b-HSD3s metabolize other substrates, which esharkgenome.imcb.a-star.edu.sg/) and Gene Indices (http:// could be novel sterols or xenobiotics. Unexpectedly, a second 11b- compbio.dfci.harvard.edu/tgi/tgipage.html) with BLAST [26] for HSD3, 11b-HSD3B, was discovered in zebrafish and fathead min- orthologs. The accessions for each gene are presented in Supple- now. Other perplexing findings emerge from this evolutionary mentary Table 1. The sequences of putative 11b-HSD3 homologs analysis. First, 11b-HSD3 is absent from the mouse and rat gen- from sea urchin, amphioxus and Ciona were re-examined for their omes. Second, there are 16 paralogs of 11b-HSD3 in amphioxus. ancestry with a BLAST search of GenBank, which found that each Thus, the evolution of 11b-HSD1 and 11b-HSD3 remains enigmatic, gene was closest to 11b-HSD3. That is, the highest scoring protein with several questions that remain to be elucidated. for each BLAST search was 11b-HSD3 and not 11b-HSD1 or another protein. Multiple alignments of 11b-HSD1 and 11b-HSD3 were done 2. Methods with Clustal X using the iteration option for each step in the multi- ple alignment [27,28]. This alignment was converted to a phyloge- We used the sequences for human 11b-HSD1 (Accession: netic tree using the neighbor-joining algorithm with a correction of DXHUBH from PIR databank) and human 11b-HSD3 (Accession: branch lengths for rate heterogeneity between sites [29]. M.E. Baker / FEBS Letters 584 (2010) 2279–2284 2281

Fig. 2. Phylogeny of deuterostomes and protostomes. Sea urchin, a basal deuterostome, contains 11b-HSD3A. There is no evidence for glucocorticoid receptors in sea urchin [25].11b-HSD3A is present in amphioxus and Ciona, while 11b-HSD1 and 11b-HSD2 are in the elephant shark. Searches of the lamprey genome did not find orthologs of 11b- HSD1, 11b-HSD3A or 11b-HSD2.

Short chain dehydrogenases/reductases (SDRs) have been clas- 3.4. Absence of 11b-HSD3 in either mouse or rat sified according to the following nomenclature: (11b-HSD1 = SDR26C1-1, 11b-HSD2 = SDR9C3-1 and 11b-HSD3 = SDR26C-2 A BLAST search of the latest mouse and rat genomes in GenBank [30]. revealed that neither genome contained 11b-HSD3, in agreement with an earlier search by Huang et al. [31]. Because the rat and mouse genomes have been extensively sequenced, it is likely that 3. Results 11b-HSD3 was lost in these rodent genomes.

3.1. Phylogenetic analysis of 11b-HSD1 and 11b-HSD3 3.5. A distant ancestor of 11b-HSD3 in a primitive metazoan

As shown in Fig. 3, the phylogeny of 11b-HSD1 and 11b-HSD3 Recently Markov et al. [25] found a distantly related ancestor of reveals that 11b-HSD3 is found in sea urchin and amphioxus. Both 11b-HSD1 in the sea anemone, Nematostella vectensis. This gene 11b-HSD1 and 11b-HSD3 are found in land vertebrates, but only (Accession: 001635085) has 35% sequence identity to human 11b-HSD3 is found in fish. BLAST searches of the elephant shark 11b-HSD3 and 11b-HSD1 over a segment of about 200 amino acids. genome found partial sequences of 11b-HSD3A and 11b-HSD1 A search of GenBank with N. vectensis 001635085 reveals that it is (Supplementary Table 2), but the sequences were not long enough closest to retinol dehydrogenases (not shown). This is in agreement to be included in the phylogenetic analysis. with other previous phylogenetic analyses showing that retinol dehydrogenases are close to 11b-HSD1, 11b-HSD2 and 17b-HSD2 3.2. Zebrafish and fathead minnow contain two isoforms of 11b-HSD3 [33,34].

There are two isoforms of 11b-HSD3 in zebrafish and fathead 4. Discussion minnow: 11b-HSD3A, the originally identified enzyme [24,31], and 11b-HSD3B, the newly identified enzyme. Thus far, only zebra- In land vertebrates, 11b-HSD1 has a critical role in glucocorti- fish and fathead minnow have been found to contain 11b-HSD3B. coid action by catalyzing the formation of cortisol, the active gluco- Fig. 4 shows the alignment of zebrafish 11b-HSD3A and 11b- corticoid, from cortisone, an inactive . As glucocorticoids HSD3B, fathead minnow 11b-HSD3B, a partial sequence of fathead have diverse and important roles in mammalian physiology [1– minnow 11b-HSD3A and human 11b-HSD1. There is excellent con- 4], and elevated glucocorticoid generation has a role in type 2 dia- servation of the 250 residue segment that constitutes the core betes and metabolic syndrome, there is considerable interest in catalytic sequence for steroid dehydrogenases. However, zebrafish developing inhibitors of 11b-HSD1. 11b-HSD3B has an additional segment at the carboxy-terminus. In the last decade, several laboratories have discovered other This additional segment in 11b-HSD3B may be important in sub- biological substrates that are metabolized by 11b-HSD1 [7–11]. cellular localization of 11b-HSD3, as has been found for the N-ter- 11b-HSD1 appears to have a physiological role that involves reduc- minal region of 11b-HSD1 [32]. tion of 7-keto-cholesterol and 7-keto-DHEA. 11b-HSD1 also metab- olizes tobacco-specific N-nitrosamines [21–23] (Fig. 1). Thus, the 3.3. Amphioxus contains 16 11b-HSD3 isoforms physiological actions and substrates of 11b-HSD1 are complex [13].

Unexpectedly there are 16 amphioxus 11b-HSD3 isoforms. Only 4.1. Evolution of 11b-HSD1 and 11b-HSD3 one amphioxus 11b-HSD3 is shown in the phylogeny in Fig. 3. The phylogeny and sequence alignment of all 16 amphioxus 11b-HSD3 Previous evolutionary analyses of 11b-HSD1 and 11b-HSD3 isoforms are shown in Supplementary Fig. 1. were intriguing because they indicated that 11b-HSD3 was the 2282 M.E. Baker / FEBS Letters 584 (2010) 2279–2284

Fig. 3. Phylogenetic analysis of 11b-hydroxysteroid dehydrogenase-type 1 and type 3. Clustal X [27,28] with 1000 bootstrap trials was used to construct the phylogenetic tree [29]. Branch lengths are proportional to the distances between each protein. Bootstrap values are the number of trials that this cluster was found in 1000 trials. Neither 11b- HSD1 nor 11b-HSD3 was found in the opossum genome. ancestral enzyme and that ray-finned fish lacked 11b-HSD1. How- catalytic activity for metabolizing cortisol to cortisone [31]. How- ever, questions remained about these conclusions because there ever, the presence of 11b-HSD1 in humans and other land verte- were few complete fish genomes available in June 2004, and dat- brates suggests that, in these vertebrates, 11b-HSD3A has other, abases such as Fugu and Ciona were not complete. Since then, as yet unknown, physiological function(s). the medaka and stickleback genomes have been sequenced, and Nevertheless, it is possible to speculate about the functions of the databases for Fugu, zebrafish and Ciona have been updated. fish 11b-HSD3A because 11b-HSD1 has not been found in fish gen- Moreover, the sea urchin and amphioxus genomes have been se- omes. Thus, it is likely that 11b-HSD3A has some 11b-HSD1-like quenced, which provide data on genes that evolved before the evo- activities in fish. These activities would appear to be converting lution of vertebrates. cortisone to cortisol and 11-KT to 11b-OH-T (Fig. 1). Cortisol is both This additional genomic information increases the reliability of a glucocorticoid and mineralocorticoid in fish, while 11-KT is the the interpretation of the phylogeny shown in Fig. 3, which indi- physiological in fish [36–40]. This suggests that 11b- cates that 11b-HSD1 was lost in ray-finned fish. The phylogeny also HSD3 has an important role in fish endocrine physiology. indicates that 11b-HSD1 evolved from an ancestral 11b-HSD3A, A perplexing finding is that there are two 11b-HSD3 isoforms in and there was a gene duplication of 11b-HSD3A in the common zebrafish and fathead minnow. Microarray studies indicate 11b- ancestor of zebrafish and fathead minnow. HSD3A is expressed in zebrafish (Baker and Hardiman, unpub- The first appearance of clear ortholog of 11b-HSD3A in sea urch- lished). Studies are underway to determine if 11b-HSD3B is ex- in, a basal deuterostome, suggests that 11b-HSD3 may have been pressed in zebrafish. important in the emergence of deuterostomes from a protostome Zebrafish 11b-HSD3A and 11b-HSD3B have about 60% sequence ancestor. The origin of 11b-HSD1 is unresolved at this time. A identity with each other, which is sufficient for them to metabolize search of the preliminary lamprey genome did not find an ortholog similar substrates, as well as for each to metabolize different sub- of either 11b-HSD1 or 11b-HSD3A or for 11b-HSD2, all of which are strates. 11b-HSD3B is longer than 11b-HSD3A, which may be present in the elephant shark genome. If indeed, 11b-HSD1 and important in localization to cellular organelles as has been found 11b-HSD2 first evolved in sharks, then this dates the evolution of for 11b-HSD1 [32]. the 11b-HSD1/11b-HSD2 mechanism for regulating tissue-specific actions of glucocorticoids [5,6,35]. 4.3. Novel functions for 11b-HSD3A in protochordates and sea urchin

4.2. Functions of 11b-HSD3: clues from the absence of 11b-HSD1 in The evolution of 11b-HSD3A in sea urchin, amphioxus and Cio- ray-finned fish na has implications for the ancestral functions of 11b-HSD3A be- cause these genomes do not contain a sequence for a At this time, little is known about the catalytic activity of 11b- glucocorticoid receptor [25]. Thus, 11b-HSD3A evolved before the HSD3. There is preliminary data that human 11b-HSD3A has weak evolution of glucocorticoid signaling. The ancestral 11b-HSD3A M.E. Baker / FEBS Letters 584 (2010) 2279–2284 2283

Fig. 4. Alignment of zebrafish and fathead minnow 11b-HSD3 isoforms with human 11b-HSD1. Only a partial sequence of fathead minnow 11b-HSD3A is available. Human 11b-HSD1 is 46% identical to zebrafish 11b-HSD3A and 48% identical to zebrafish 11bHSDB. Zebrafish 11bHSDA and 11b-HSDB are 58% identical. Zebrafish 11b-HSDB and fathead minnow 11b-HSDB are 82% identical. may have metabolized novel oxysterols [7,9,11,17,25] or xenobiot- pressed, and if all of the expressed isoforms have catalytic ics [21–23,25,41], as has been found for 11b-HSD1 (Fig. 1). That is, activity. Moreover, their function is not clear because glucocorti- one or more of the newly described ‘‘alternative” functions of 11b- coids have not been found in amphioxus [42]. It may be that some HSD1 [13] may be related to an ancestral function of 11b-HSD3A. amphioxus 11b-HSD3s are involved in metabolism of xenobiotics or in regulating the concentrations of novel ligands for transcrip- 4.4. Absence of 11b-HSD3 in either mouse or rat tion factors.

The absence of 11b-HSD3 in mouse or rat is surprising [31]. Be- cause both rodent genomes have been extensively sequenced, it Acknowledgment seems unlikely that 11b-HSD3 is in the mouse or rat genomes. The absence in mice of 11b-HSD3 provides an opportunity to I thank Scott Wu for help in collecting 11b-HSD1 and 11b-HSD3 investigate its role by insertion this gene in mice lacking functional from databases. 11b-HSD1. Appendix A. Supplementary data 4.5. Multiple isoforms of 11b-HSD3A in amphioxus Supplementary data associated with this article can be found, in A very surprising finding is that amphioxus contains 16 para- the online version, at doi:10.1016/j.febslet.2010.03.036. logs of 11b-HSD3A. It is not known if all of these isoforms are ex- 2284 M.E. Baker / FEBS Letters 584 (2010) 2279–2284

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